Brain tumors occur in the skull, and include primary brain tumors and metastatic brain tumors. Primary brain tumors are tumors which originate in brain tissue, and metastatic brain tumors are tumors caused by metastasis of tumors formed in other organs to brain tissue. Primary brain tumors include benign tumors and malignant tumors.
Malignant primary brain tumors grow rapidly. Further, because this type of tumor infiltrates into brain tissue, it is hard to identify the border between the tumor and normal tissue, and it is difficult to completely remove the tumor cells by surgery. Accordingly, for highly malignant tumors, radiotherapy and chemotherapy are further used after surgery, in order to treat tumors that cannot be completely removed by surgery.
Benign primary brain tumors rarely grow rapidly; however, the internal volume of the skull is limited, and the intracranial pressure is thus accelerated due to the growth of the tumor, thereby causing headaches and nausea. Depending on the location of tumor, paralysis, dysbasia, speech disorder, dyskinesia, visual impairment, and like symptoms may occur.
Benign primary brain tumors generally have a clear border with normal tissue, and can be treated by surgical removal. However, fusion and infiltration of a tumor to surrounding important nerve tissue may occur depending on the tumor location, and such tumors cannot be completely removed, thereby leading to recurrence in some cases. When the tumor cannot be completely removed, radiation therapy is applied to prevent recurrence, as in the case of malignant tumors. Radiation therapy includes whole-brain radiotherapy and stereotactic radiotherapy. Whole-brain radiotherapy may lead to a development of dementia later in life. Compared with whole-brain radiotherapy, stereotactic radiotherapy may lead to a formation of new metastatic lesions. For infants, there is also a problem of intellectual underdevelopment caused by radiation therapy.
Metastatic brain tumors are treated by using removal surgery, radiation therapy, and chemotherapy, in combination, although it depends on the treatment protocol of the primary tumor.
Drugs currently used in chemotherapy include temozolomide, procarbazine, carmustine, nimustine, and ranimustine, which are alkylating agents, and bevacizumab, which is a vascularization inhibitor. However, these drugs are not satisfactory in their therapeutic effects, and more effective drugs are desired.
In order for brain tumor therapeutic agents to exhibit their effects, it is necessary to deliver the drug into the brain. For this purpose, the drug must penetrate the blood-brain barrier. If the drug cannot sufficiently be delivered to the brain, recurrence of the tumor may occur from tumor cells that cannot be removed by surgery. However, there is a restriction to a chemical structure of the drug; for example, it is required for the drug to have a small molecular weight to pass through the blood-brain barrier. This makes the development of brain tumor therapeutic agents difficult.
Cancer cells and cancer microenvironment have various immune checkpoint molecules that prevent immune responses against cancer. Immune checkpoint inhibitors have the action of inhibiting immune checkpoint molecules to block the immunosuppression mechanism, thereby activating immune responses against cancer. Accordingly, immune checkpoint inhibitors are used as therapeutic agents for cancer. As immune checkpoint inhibitors, nivolumab, pembrolizumab, etc., which are anti-PD-1 antibodies, have already been approved and available in the market in Japan and internationally.
Patent Document 1 teaches that Compound A (to be described later) strongly binds to an EP4 receptor, and shows an antagonistic activity; however, Patent Document 1 does not describe or suggest effects of treating brain tumors.